Amphiphilic star-like macromolecules for drug delivery

ABSTRACT

The present invention provides polymeric compounds that can form micelles in solutions. These compounds have a hydrophobic, core that is coupled to a plurality of hydrophilic moieties.

PRIORITY OF INVENTION

[0001] This application claims the benefit of the filing date of U.S.application Serial No. 60/304,965, filed Jul. 12, 2001 and U.S.application Serial No. 60/333,310, filed Nov. 23, 2001, under 35 U.S.C.§ 119(e), the disclosures of which are incorporated by reference hereinin their entirety

GOVERNMENT FUNDING

[0002] The invention described herein was made with government supportunder Grant Number 99-83272, awarded by the National Science Foundation.The United States Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0003] Currently, there is a need for methods for deliveringpharmaceutically active agents to patients in need of the active agent.One method for delivery is to encapsulate an active agent, such as, forexample, a hydrophobic molecule in a polymer molecule wherein thepolymer has a core that is coupled to a plurality of hydrophobicmoieties.

[0004] Amphiphilic star-like macromolecules (ASMs) have been studied fordrug delivery applications. (See, e.g., U.S. patent application Ser. No.09/298,729 filed Apr. 23, 1999; U.S. patent application Ser. No.09/422,295, filed Oct. 21, 1999, and International Patent ApplicationUS00/10050 filed Apr. 18, 2000.) The core-shell, amphiphilic structureof ASMs is covalently linked, which makes it thermodynamically stable asopposed to conventional micellar systems. Previously, aromatic coreswere incorporated within the ASM structure but proved to be cytotoxicupon its degradation.

[0005] Polymeric micelles are a related type of amphiphilic blockcopolymers. These micelles have attracted attention as promisingcolloidal drug delivery systems (V. P. Torchilin J. Controlled. Release.2001, 73, 137; C. Allen, D. et al., Colloids and Surfaces B:Biointerfaces 1999, 16, 3; and H. Otsuka, et al., Current Opinion inColloid & Interface Science 2001, 6, 3). In these colloidal systems, thehydrophobic block typically forms the core, essentially a“microcontainer” for a lipophilic pharmaceutical (K. Kataoka, et al.,Adv. Drug Delivery Rev. 2001, 47, 113). The hydrophilic part forms theouter shell, stabilizing the interface between the core and the externalaqueous environment. Compared to traditional micellar systems, thesepolymeric surfactant-based drug carriers display apparent advantagessuch as lower critical micelle concentration (CMC), improvedbioavailability, reduction of toxicity, enhanced permeability across thephysiological barriers, and substantial changes in drug biodistribution.

[0006] Despite these advantages, the use of ASM's is somewhat limited,due to the difficulty in directing the release of the active agent at ornear an appropriate target. Accordingly, there is a need for additionalmicellar systems and reverse micellar systems that possess some of theadvantages associated with the thermodynamic stability of ASM's, butwhich can be used to direct active agents to specific targets.

SUMMARY OF THE INVENTION

[0007] The present invention provides a compound having formula (I):

R¹—((R²)_(a)—(R³)_(b)—(R⁴)_(c)—(R⁵)_(d)—(R⁶)_(e))_(n)  (I)

[0008] wherein:

[0009] a) R¹ is a core comprising a polyol or polyacid;

[0010] each R² independently is a divalent or polyvalent group havingthe formula —X¹—R⁸—(X^(1a))_(g)—, wherein X¹ and X^(1a) areindependently —C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent, and each R⁸is independently —(C₁₋₈)alkylene-, branched —(C₁₋₈)alkylene- or—(C₆₋₁₀)aryl-; a is 0 or an integer from 1 to about 10; and g is aninteger from 1 to about 6;

[0011] each R³ independently is a divalent dicarboxylic acid moietyhaving the formula —C(═O)—R⁹—C(═O)—, wherein R⁹ is an alkylene orcycloalkylene group containing from 1 to about 15 carbon atoms,substituted with a total of from 1 to about 10 hydroxy groups, whereinone or more of the hydroxy groups of the dicarboxylic acid are acylatedwith an acid residue; and b is an integer from 1 to about 10;

[0012] each R⁴ independently is a divalent or polyvalent group havingthe formula —X²R¹⁰—(X^(2a))_(h)—, wherein X² is —C(═O)—, —C(═S)—, —O—,—S—, —N(R⁷)— or absent; X^(2a) is —C(═O)—, —C(═S)—, —O—, —S—, or —N(R⁷)—and R¹⁰ is —(C₁₋₈)alkylene-, branched —(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-;and c is 0 or an integer from 1 to about 10; and h is an integer from 1to 6;

[0013] each R⁵ independently is a group having the formula:

—R¹²—(R¹¹)_(f)—R¹²—X³—

[0014] wherein R¹¹ is a sugar moiety; or a poly(alkylene oxide) orpoly(alkylene imine) group having the formula —(—X⁴—R¹³)—; wherein R¹³is —(C₂₋₄₀)alkylene- or branched —(C3₋₄₀)alkylene-; wherein each X³ isindependently —C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent; each X⁴ isindependently —O—, or —N(R⁷)—; and f is an integer from about 2 to about150; and d is from 1 to about 6;

[0015] each R¹² is independently a bond, —(C₁₋₄₀)alkylene- or branched—(C₁₋₄₀)alkylene-groups, wherein each R¹² is optionally substituted withone or more (e.g., 1, 2, or 3) functional groups. The functional groupsare —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H (sulfo), —CH₂—OH,—CH₂—OR^(a), —CH₂—O—CH₂—R^(a), and —CH₂—NR^(a)R^(b); and X⁴ is —O—, —S—,or —N(R⁷)—;

[0016] wherein n is from 2 to 12; provided that a and b are not bothzero; wherein each R⁷ is independently selected from the groupconsisting of hydrogen, and C₍₁₋₄₀₎alkyl group, where the alkyl groupcan be a straight-chain or branched group; and R^(a) and R^(b) are eachindependently hydrogen (C₁₋₈)alkyl, aryl, aryl(C₁₋₈)alkylene; and

[0017] R⁶ is hydrogen, are —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H(sulfo), —CH₂—OH, —CH₂OR^(a), —CH₂—O—CH₂—R^(a), —CH₂—R^(a)R^(b) or atargeting moiety; provided that at least one R⁶ group is a targetingmoiety; and e is from 1 to about 6:

[0018] b) R¹ is a core comprising a polyol or polyacid;

[0019] each R² independently is a divalent or polyvalent group havingthe formula —X¹R⁸(X^(1a))_(g)—, wherein X¹ and X^(1a) are independently—C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent, and each R⁸ isindependently —(C₁₋₈)alkylene-, branched —(C₁₋₈)alkylene- or—(C₆₋₁₀)aryl-; a is an integer from 1 to about 10; and g is an integerfrom 1 to about 6;

[0020] each R³ independently is a divalent dicarboxylic acid moietyhaving the formula —C(═O)—R⁹—C(═O)—, wherein R⁹ is an alkylene orcycloalkylene group containing from 1 to about 15 carbon atoms,substituted with a total of from 1 to about 10 hydroxy groups, whereinone or more of the hydroxy groups of the dicarboxylic acid are acylatedwith an acid residue; and b is an integer from 1 to about 10;

[0021] each R⁴ independently is a divalent or polyvalent group havingthe formula —X²—R—(X^(2a))_(h)—, wherein X² is —C(═O)—, —C(═S)—, —O—,—S—, —N(R⁷)— or absent; X^(2a) is —C(═O)—, —C(═S)—, —O—, —S—, or —N(R⁷)—and R¹⁰ is —(C₁₋₈)alkylene-, branched —(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-;and c is 0 or an integer from 1 to about 10; and h is an integer from 1to 6;

[0022] each R⁵ independently is a group having the formula:

—R¹²—(R¹¹)_(f)—R¹²—X³—

[0023] wherein R¹¹ is a sugar moiety; or a poly(alkylene oxide) orpoly(alkylene imine) group having the formula —(—X⁴—R¹³)—; wherein R¹³is —(C₂₋₄₀)alkylene- or branched —(C₃₋₄₀)alkylene-; wherein each X³ isindependently —C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent; each X⁴ isindependently —O—, or —N(R⁷)—; and f is an integer from about 2 to about150; and d is from 1 to about 6;

[0024] each R¹² is independently a bond, —(C₁₋₄₀)alkylene- or branched—(C₁₋₄₀)alklylene-groups, wherein each R¹² is optionally substitutedwith one or more (e.g., 1, 2, or 3) functional groups. The functionalgroups are —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H (sulfo), —CH₂—OH,—CH₂OR^(a), —CH₂—O—CH₂—R^(a), and CH₂—NR^(a)R^(b); and X⁴ is —O—, —S—,or —N(R⁷)—;

[0025] wherein n is from 2 to 12; provided that a and b are not bothzero; wherein each R⁷ is independently selected from the groupconsisting of hydrogen, and C₍₁₋₄₀)alkyl group, where the alkyl groupcan be a straight-chain or branched group; and R^(a) and R^(b) are eachindependently hydrogen (C₁₋₈)alkyl, aryl, aryl(C₁₋₈)alkylene; and

[0026] R⁶ is hydrogen, are —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H(sulfo), —CH₂—OH, —CH₂—OR^(a), —CH₂—O—CH₂—R^(a), —CH₂—NR^(a)R^(b) or atargeting moiety; and e is from 1 to about 6:

[0027] c) R¹ is a core comprising a polyol or polyacid;

[0028] each R² independently is a divalent or polyvalent group havingthe formula —X¹—R⁸—(X^(1a))_(g)—, wherein X¹ and X^(1a) areindependently —C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent, and each R⁸is independently —(C₁₋₈)alkylene-, branched —(C₁₋₈)alkylene- or—(C₆₋₁₀)aryl-; a is 0 or an integer from 1 to about 10; and g is aninteger from 1 to about 6;

[0029] each R³ independently is a divalent dicarboxylic acid moietyhaving the formula —C(═O)—R⁹—C(═O)—, wherein R⁹ is an alkylene orcycloalkylene group containing from 1 to about 15 carbon atoms,substituted with a total of from 1 to about 10 hydroxy groups, whereinone or more of the hydroxy groups of the dicarboxylic acid are acylatedwith an acid residue; and b is an integer from 1 to about 10;

[0030] each R⁴ independently is a divalent or polyvalent group havingthe formula —X²—R¹⁰—(X^(2a))_(h)—, wherein X² is —C(═O)—, —C(═S)—, —O—,—S—, —N(R⁷)— or absent; X^(2a) is —C(═O)—, —C(═S)—, —O—, —S—, or —N(R⁷)—and R¹⁰ is —(C₁₋₈)alkylene-, branched —(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-;and c is an integer from 1 to about 10; and h is an integer from 1 to 6;

[0031] each R⁵ independently is a group having the formula:

—R¹²—(R¹¹)_(f)—R¹²—X³—

[0032] wherein R¹¹ is a sugar moiety; or a poly(alkylene oxide) orpoly(alkylene imine) group having the formula —(—X⁴—R¹³)—; wherein R¹³is —(C₂₋₄₀)alkylene- or branched —(C₃₋₄₀)alkylene-; wherein each X³ isindependently —C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent; each X⁴ isindependently —O—, or —N(R⁷)—; and f is an integer from about 2 to about150; and d is from 1 to about 6;

[0033] each R¹² is independently a bond, —(C₁₋₄₀)alkylene- or branched—(C₁₋₄₀)alkylene-groups, wherein each R¹² is optionally substituted withone or more (e.g., 1, 2, or 3) functional groups. The functional groupsare —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H (sulfo), —CH₂—OH,—CH₂—OR^(a), —CH₂—O—CH₂—R^(a), and —CH₂—NR^(a)R^(b); and X⁴ is —O—, —S—,or —N(R⁷)_;

[0034] wherein n is from 2 to 12; provided that a and b are not bothzero; wherein each R⁷ is independently selected from the groupconsisting of hydrogen, and C₍₁₋₄₀₎alkyl group, where the alkyl groupcan be a straight-chain or branched group; and R^(a) and R^(b) are eachindependently hydrogen (C₁₋₈)alkyl, aryl, aryl(C₁₋₈)alkylene; and

[0035] R⁶ is hydrogen, are —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H(sulfo), —CH₂—OH, —CH₂—OR^(a), —CH₂—O—CH₂—R^(a), —CH₂—NR^(a)R^(b) or atargeting moiety; and e is from 1 to about 6:

[0036] d) R¹ is a core comprising a polyacid moiety having the formula

[0037] or a pentaerythritol polyol having the formula

[0038] wherein each R² independently is a divalent or polyvalent grouphaving the formula —X¹—R⁸—(X^(1a))_(g)—, wherein X¹ and X^(1a) areindependently —C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent, and each R⁸is independently —(C₁₋₈)alkylene-, branched —(C₁₋₈)alkylene- or—(C₆₋₁₀)aryl-; a is 0 or an integer from 1 to about 10; and g is aninteger from 1 to about 6;

[0039] each R³ independently is a divalent dicarboxylic acid moietyhaving the formula —C(═O)—R⁹—C(═O)—, wherein R⁹ is an alkylene orcycloalkylene group containing from 1 to about 15 carbon atoms,substituted with a total of from 1 to about 10 hydroxy groups, whereinone or more of the hydroxy groups of the dicarboxylic acid are acylatedwith an acid residue; and b is an integer from 1 to about 10;

[0040] each R⁴ independently is a divalent or polyvalent group havingthe formula —X²—R¹⁰—(X^(2a))_(h)—, wherein X² is —C(═O)—, —C(═S)—, —O—,—S—, —N(R⁷)— or absent; X^(2a) is —C(═O)—, —C(═S)—, —O—, —S—, or —N(R⁷)—and R¹⁰ is —(C₁₋₈)alkylene-, branched —(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-;and c is 0 or an integer from 1 to about 10; and h is an integer from 1to 6;

[0041] each R⁵ independently is a group having the formula:

—R¹²—(R¹¹)_(f)—R¹²—X³—

[0042] wherein R¹¹ is a sugar moiety; or a poly(alkylene oxide) orpoly(alkylene imine) group having the formula —(—X⁴—R³)—; wherein R¹³ is—(C₂₋₄₀)alkylene- or branched —(C₃₋₄₀)alkylene-; wherein each X³ isindependently —C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷_or absent; each X⁴ isindependently —O—, or —N(R⁷)—; and f is an integer from about 2 to about150; and d is from 1 to about 6;

[0043] each R¹² is independently a bond, —(C₁₋₄₀)alkylene- or branched—(C₁₋₄₀)alkylene-groups, wherein each R¹² is optionally substituted withone or more (e.g., 1, 2, or 3) functional groups. The functional groupsare —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H (sulfo), —CH₂—OH,—CH₂—OR^(a), —CH₂—O—CH₂—R^(a), and —CH₂—NR^(a)R^(b); and X⁴ is —O—, —S—,or —N(R⁷)—;

[0044] wherein n is from 2 to 12; provided that a and b are not bothzero; wherein each R⁷ is independently selected from the groupconsisting of hydrogen, and C₍₁₋₄₀₎alkyl group, where the alkyl groupcan be a straight-chain or branched group; and R^(a) and R^(b) are eachindependently hydrogen (C₁₋₈)alkyl, aryl, aryl(C₁₋₈)alkylene; and

[0045] R⁶ is hydrogen, are —OH, —OR^(a), —NR^(a)R^(b), —NH₂, —CO₂H,—SO₃H (sulfo), —CH₂—OH, —CH₂—OR^(a), —CH₂—O—CH₂—R^(a)—CH₂—NR^(a)R^(b) ora targeting moiety; and e is from 1 to about 6.

[0046] Additionally, compounds of formula (I) having unsaturated bonds(e.g., in the fatty acid or polyether groups), can be cross-linked toform covalently bonds in the hydrophobic portion.

[0047] Accordingly, the invention provides a compound of formula (I) asdescribed above. Such compounds of formula (I) are useful intermediatesfor preparing micelles that can be used in drug delivery applicationsand that can be cross-linked to provide cross-linked macromolecules thatare also useful in drug delivery applications.

[0048] The invention also provides an encapsulate comprising a moleculesurrounded or partially surrounded by a macromolecule of the invention.

[0049] The invention also provides a method for preparing an encapsulateof the invention comprising combining compounds of fonrula (I) and amolecule (e.g., a therapeutic agent) in a solvent, and allowing thecompounds of formula (1) to aggregate around the molecule, to providethe encapsulate (i.e., the molecule surrounded or partially surroundedby compounds of formula (I)).

[0050] The invention also provides a pharmaceutical compositioncomprising an encapsulate of the invention (i.e., a therapeutic agentsurrounded or partially surrounded by compounds of formula (I)); and apharmaceutically acceptable carrier.

[0051] The invention also provides a pharmaceutical compositioncomprising an encapsulate of the invention (i.e., a therapeutic agentencapsulated in a cross-linked macromolecule); and a pharmaceuticallyacceptable carrier.

[0052] The invention also provides a method for modulating the releaseof a therapeutic agent from a pharmaceutical composition comprisingadministering an encapsulate of the invention to an animal in need oftreatment. The encapsulate can modulate the release of therapeuticagents by controlling the adsorption of the active agent encapsulatedwithin the encapsulate through the skin of the animal.

[0053] The invention also provides a method for delivering a therapeuticagent to an animal in need of treatment with the agent comprisingadministering an encapsulate of the invention comprising the agent tothe animal.

[0054] The invention also provides intermediates and processes usefulfor preparing compounds of formula (I) as described herein.

[0055] The invention also provides for the use of a compound of formula(I) to prepare a medicament useful for treating or preventing an illnessor a disease.

[0056] The invention also provides a method for using a compound offormula (I) to (a) sequester lipoproteins from macromolecular depotssuch as proteoglycans that heighten atherogenic tendencies; (b) reducelipoprotein oxidation (which leads to unregulated uptake of low-densitylipoproteins (LDL) by macrophages, transforming them into foam cells,the precursors to atherosclerosis); and (c) enhance lipoproteintransport and clearance (via macrophages, and the liver). The compoundshaving formula (I) can be administered to a patient in need of reducingthe concentration of lipoproteins and minimize cardiovascular diseasescaused by the presence of excess LDL in the blood.

BRIEF DESCRIPTION OF THE FIGURES

[0057]FIGS. 1 and 2 illustrate representative reactions for attachingthe targeting moiety, biotin, to a polyalkylene oxide (R⁵) group.

[0058]FIG. 3 illustrates a representative reaction for acylation of adivalent dicarboxylic acid moiety, (R³ group).

[0059]FIG. 4 illustrates a representative reaction for attaching R³groups to prepare a compound of the invention.

[0060]FIG. 5 illustrates two compounds that can be incorporated in thecompounds of the invention as targeting moieties.

[0061]FIG. 6 illustrates a representative reaction for attaching apolyethylene oxide (R⁵) group to prepare a compound of the invention.

[0062]FIG. 7 illustrates a representative reaction for cross-linking thecompounds of the invention having unsaturation in the R groups toprepare a covalently stabilized compound of the invention.

[0063]FIGS. 8, 9, 10, and 11 illustrate representative compounds of theinvention.

DETAILED DESCRIPTION

[0064] As used herein the term “polyol” includes straight chain andbranched chain aliphatic groups, as well as mono-cyclic and poly-cyclicaliphatics, which are substituted with two or more hydroxy groups. Apolyol typically has from about 2 carbons to about 20 carbons;preferably, from about 3 carbons to about 12 carbons; and morepreferably from about 4 carbons to about 10 carbons. A polyol alsotypically comprises from about 2 to about 20 hydroxy groups; preferablyfrom about 2 to about 12 hydroxy groups; and more preferably from about2 to about 10 hydroxy groups. A polyol can also optionally besubstituted on a carbon atom with one or more (e.g., 1, 2, or 3) carboxygroups (COOH). These carboxy groups can conveniently be used to link thepolyol to the polyether in a compound of formula (I).

[0065] Polyols that are suitable for use as the polymer core are nearlylimitless. Aliphatic polyols having from 1 to 10 carbon atoms and from 1to 10 hydroxyl groups may be used, including ethylene glycol, alkanediols, alkyl glycols, alkylidene alkyl diols, alkyl cycloalkane diols,1,5-decalindiol, 4,8-bis(hydroxymethyl)tricyclodecane, cycloalkylidenediols, dihydroxyalkanes, trihydroxyalkanes, and the like. Cycloaliphaticpolyols may also be employed, including straight chained or closed-ringsugars and sugar alcohols, such as mannitol, sorbitol, inositol,xylitol, quebrachitol, tlheitol, arabitol, erythritol, adonitol,dulcitol, fucose, ribose, arabinose, xylose, lyxose, rhanmose,galactose, glucose, fructose, sorbose, mannose, pyranose, altrose,talose, tagitose, pyranosides, sucrose, lactose, maltose, and the like.Additional examples of aliphatic polyols include derivatives ofglyceraldehyde, glucose, ribose, mannose, galactose, and relatedstereoisomers.

[0066] Other R¹ polyols that may be used include cyclic crown ethers,cyclodextrines, dextrines and other carbohydrates such as starches andamylose. Alkyl groups may be straight-chained or branched, and maycontain from 1 to 10 carbon atoms.

[0067] The term “polyacids” as used herein include compounds which havetwo or more acid groups per molecule. Preferably, the polyacid is adibasic, tribasic or polybasic carboxylic acid functional compound. Thepolyacid can generally be aliphatic, cycloaliphatic or aromatic.Examples of polyacids include compound such as cyclodextrans andcalerixane.

[0068] Specific R³ groups are formed from di-carboxylic acids containingfrom 1 to about 10 carbon atoms and substituted with from 1 to about 10hydroxyl groups. The mono-or di-carboxylic acid may be a straightchained or branched chained aliphatic, or a mono-cyclic or poly-cyclicaliphatic compound. Suitable dicarboxylic acids include mucic acid,malic acid, citromalic acid, alkylmalic acid, hydroxy derivatives ofglutacic acid, and alkyl glutadc acids, tartadc acid, citric acid,hydroxy derivatives of rumadc acid, and the like. Suitablemonocarboxylic acids include 2,2-(bis(hydroxymethyl)propionic acid, andN-[tris(hydroxymethyl)methyl]glycine (tricine).

[0069] Specific “sugar moieties” include monosaccharides, disaccharides,trisaceharides, and polysaccharides. Non-limiting examples of sugarmoieties include straight chained or closed-ring sugars and sugaralcohols, such as, for example, mannitol, sorbitol, inositol, xylitol,quebrachitol, tlreitol, arabitol, erythritol, adonitol, dulcitol,fucose, ribose, arabinose, xylose, lyxose, rhanmose, galactose, glucose,fructose, sorbose, mannose, pyranose, altrose, talose, tagitose,pyranosides, sucrose, lactose, maltose, and the like. Additionalexamples of aliphatic polyols include derivatives of glyceraldehyde,glucose, ribose, mannose, galactose, and related stereoisomers.Preferred sugar moieties are glucose, sucrose, fructose, ribose, and thelike, and deoxy sugars such as deoxyribose, and the like. Saccharidederivatives can conveniently be prepared by methods known to the art.Examples of suitable mono-saccharides are xylose, arabinose, ribose, andthe like. Examples of di-saccharides are maltose, lactose, sucrose, andthe like. Examples of suitable sugar-alcohols are erythritol, sorbitol,and the like.

[0070] As used herein, the term polyether includes poly(alkylene oxides)having between about 2 and about 150 repeating units. Typically, thepoly(alkylene oxides) have between about 50 and about 110 repeatingunits. The alkylene oxide units contain from 2 to 10 carbon atoms andmay be straight chained or branched. Preferably, the alkylene oxideunits contain from 2 to 10 carbon atoms. Poly(ethylene glycol) (PEG) ispreferred. Alkoxy-, amino-, carboxy-, and sulfo-terminated poly(alkyleneoxides) are preferred.

[0071] In a compound of formula (I), a poly(alkylene oxide) can belinked to a polyol, for example, through an ether, thioether, amine,ester, thioester, thioamide, or amide linkage. Preferably, apoly(alkylene oxide) is linked to R³ by an ester or amide linkage in acompound of formula (I).

[0072] As used herein, the term polyimine includes poly(alkylene imines)having between about 2 and about 150 repeating units. Typically, thepoly(alkylene imines) have between about 50 and about 110 repeatingunits. The alkylene imine units contain from 2 to 10 carbon atoms andmay be straight chained or branched. Preferably, the alkylene imineunits contain from 2 to 10 carbon atoms. Poly(ethylene imine) (PEI) ispreferred. Alkoxy-, amino-, carboxy-, and sulfo-terminated poly(alkyleneimines) are preferred.

[0073] In a compound of formula (I), a poly(alkylene imine) can belinked to a polyol, for example, through an ether, thioether, amine,ester, thioester, thioamide, or amide linkage. Preferably, apoly(alkylene imine) is linked to R³ by an ester or amide linkage in acompound of formula (I).

[0074] As used herein, the term “targeting moiety” refers to groups thathave an ability to direct the encapsulated active agents to a site wherethe activity from the active agent is desired. In the present inventionthe polymers can have one or more targeting moiety. Non-limitingexamples of targeting moieties include but are not limited to groupssuch as, for example, —CO₂H, —SO₃H (sulfo), —NH₂, or groups derived fromcompounds such as, for example, biotin, streptavidin, sugar moieties,folic acid, amino acids and peptides.

[0075] As used herein, the term fatty acid includes fatty acids andfatty oils as conventionally defined, for example, long-chain aliphaticacids that are found in natural fats and oils. Fatty acids typicallycomprise from about 2 to about 24 carbon atoms. Preferably, fatty acidscomprise from about 6 to about 18 carbon atoms. The term “fatty acid”encompasses compounds possessing a straight or branched aliphatic chainand an acid group, such as a carboxylate, sulfonate, phosphate,phosphonate, and the like. The “fatty acid” compounds are capable of“esterifying” or forming a similar chemical linkage with hydroxy groupson the polyol. Examples of suitable fatty acids include caprylic,capric, lauric, myristic, myristoleic, palmitic, palmitoleic, stearic,oleic, linoleic, eleostearic, arachidic, behenic, erucic, and likeacids. Fatty acids can be derived from suitable naturally occurring orsynthetic fatty acids or oils, can be saturated or unsaturated, and canoptionally include positional or geometric isomers. Many fatty acids oroils are commercially available or can be readily prepared or isolatedusing procedures known to those skilled in the art.

[0076] As used herein the term “amino acid,” comprises the residues ofthe natural amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly,His, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, andVal) in D or L form, as well as unnatural amino acids (e.g.phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline,gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylicacid, statine, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid,penicillamine, ornithine, citruline, a-methyl-alanine,para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine,and tert-butylglycine). The term also comprises natural and unnaturalamino acids bearing a conventional amino protecting group (e.g. acetylor benzyloxycarbonyl), as well as natural and unnatural amino acidsprotected at the carboxy terminus (e.g., as a (C₁-C₆)alkyl, phenyl orbenzyl ester or amide, or as an *-methylbenzyl amide). Other suitableamino and carboxy protecting groups are known to those skilled in theart (See for example, T. W. Greene, Protecting Groups In OrganicSynthesis; Wiley: New York, 1981, and references cited therein). Anamino acid can be linked to the remainder of a compound of formula Ithrough the carboxy terminus, the amino terminus, or through any otherconvenient point of attachment, such as, for example, through the sulfurof cysteine.

[0077] As used herein, the term “peptide” describes a sequence of 2 to25 amino acids (e.g., as defined hereinabove) or peptidyl residues. Thesequence may be linear or cyclic. For example, a cyclic peptide can beprepared or may result from the formation of disulfide bridges betweentwo cysteine residues in a sequence. A peptide can be linked to theremainder of a compound of formula I through the carboxy terminus, theamino terminus, or through any other convenient point of attachment,such as, for example, through the sulfur of a cysteine. Preferably apeptide comprises 3 to 25, or 5 to 21 amino acids. Peptide derivativescan be prepared as disclosed in U.S. Pat. Nos. 4,612,302; 4,853,371; and4,684,620. Peptide sequences specifically recited herein are writtenwith the amino terminus on the left and the carboxy terminus on theright.

[0078] It is understood that in the compounds of the invention where R²is a polyvalent moiety one valence is attached to R¹ and each of theother valences is attached to a group having the formula—(R³)_(b)—(R⁴)_(c)—(R⁵)_(d)—(R⁶)_(e) where each R³, R⁴, R⁵, R⁶, b, c, d,and e independently have the meanings described herein above.

[0079] It is understood that in the compounds of the invention where R⁴is a polyvalent moiety one valence is attached to R³ and each of theother valences is attached to a group having the formula—(R⁵)_(d)—(R⁶)_(e) where each R⁵, R⁶, d, and e independently have themeanings described herein above.

[0080] As used herein, a “cross-linked macromolecule” means a micellethat has been cross-linked to provide a covalently cross-linkedstructure.

[0081] As used herein, the term “encapsulate” means a composition,having a molecule (e.g., a therapeutic agent) surrounded or partiallysurrounded by at least one compound of formula (I). The term encapsulateincludes structures wherein the compound of formula (I) has beencross-linked, as well as structures wherein the compound of formula (I)has not been cross-linked.

[0082] The compounds of formula (I) that comprise unsaturated bonds canbe cross-linked to form more stabilized polymers, which comprise acompound of formula (I) that have been covalently linked.

[0083] Typically, the polymers of the invention have a diameter of fromabout 10 nm to about 1000 nm. The diameters can be measured using anysuitable analytical technique, such as, for example, dynamic lightscattering.

[0084] Compounds of formula (I) can be used for drug solubilization,fragrance encapsulation, passive and active targeting for drug delivery,waste water treatment, enhanced capillary electrophoresis activation,and induction of protein crystallization.

[0085] Accordingly, as used herein, the term “molecule” includes anycompound that can be incorporated into a polymer or a cross-linkedpolymer as described herein. Typically, “molecules” have solubilityproperties that are undesirable and that can be modified byincorporation into an amphiphilic polymer or a cross-linked polymer ofthe invention. For example, the term “molecule” includes therapeuticagents, insecticides, pesticides, herbicides, antiseptics, foodadditives, fragrances, dyes, diagnostic aids, and the like. Otherspecific examples of molecules include, but are not limited to:

[0086] abietic acid, aceglatone, acenaphthene, acenocoumarol,acetohexamide, acetomeroctol, acetoxolone, acetyldigitoxins, acetylenedibromide, acetylene dichloride, acetylsalicylic acid, alantolactone,aldrin, alexitol sodium, allethrin, allylestrenol, allyl sulfide,alprazolam, aluminum bis(acetylsalicylate), ambucetamide,aminochlothenoxazin, aminoglutethimide, amyl chloride, androstenediol,anethole trithone, anilazine, anthralin, Antimycin A, aplasmomycin,arsenoacetic acid, asiaticoside, astemizole, aurodox, aurothioglycamide,8-azaguanine, azobenzene;

[0087] baicalein, Balsam Peru, Balsam Tolu, barban, baxtrobin, bendazac,bendazol, bendroflumethiazide, benomyl, benzathine, benzestrol,benzodepa, benzoxiquinone, benzphetamine, benzthiazide, benzyl benzoate,benzyl cinnamate, bibrocathol, bifenox, binapacryl, bioresmethrin,bisabolol, bisacodyl, bis(chlorophenoxy)methane, bismuth iodosubgallate,bismuth subgallate, bismuth tannate, Bisphenol A, bithionol, bomyl,bromoisovalerate, bomyl chloride, bomyl isovalerate, bomyl salicylate,brodifacoum, bromethalin, broxyquinoline, bufexamac, butaunirate,butethal, buthiobate, butlated hydroxyanisole, butylated hydroxytoluene;

[0088] calcium iodostearate, calcium saccharate, calcium stearate,capobenic acid, captan, carbamazepine, carbocloral, carbophenothin,carboquone, carotene, carvacrol, cephaeline, cephalin, chaulmoogficacid, chenodiol, chitin, chlordane, chlorfenac, chlorfenetbol,chlorothalonil, chlorotrianisene, chlorprothixene, chlorquinaldol,chromonar, cilostazol, cinchonidine, citral, clinofibrate, clofazimine,clofibrate, cloflucarban, cionitrate, clopidol, clorindione, cloxazolam,coroxon, corticosterone, coumachlor, coumaphos, coumithoate cresylacetate, crimidine, criformate, cuprobam, cyameniazine, cyclandelate,cyclarbamate cymarin, cypennethril;

[0089] dapsone, defosfamide, deltamethrin, deoxycorticocosteroneacetate, desoximetasone, dextromoramide, diacetazoto, dialifor,diathymosulfone, decapthon, dichlofluani, dichlorophen,dichlorphenamide, dicofol, dicryl, dicmarol, dienestrol,diethylstilbestrol, difenamizole, dihydrocodeinone enol acetate,dihydroergotamine, dihydromorphine, dihydrotachysterol, dimestrol,dimethisterone, dioxathion, diphenane,N-(1,2-diphenylethyl)nicofinamide, dipyrocetyl, disulfamide, dithianone,doxenitoin, drazoxolon, durapatite, edifenphos, emodin, enfenamic acid,erbon, ergocorninine, erythrityl tetranitrate, erythromycin stearate,estriol, ethaverine, ethisterone, ethyl biscomacetate,ethylhydrocupreine, ethyl menthane carboxamide, eugenol, euprocin,exalamide;

[0090] febarbamate, fenalamide, fenbendazole, fenipentol, fenitrothion,fenofibrate, fenquizone, fenthion, feprazone, flilpin, filixic acid,floctafenine, fluanisone, flumequine, fluocortin butyl, fluoxymesterone,flurothyl, flutazolam, fumagillin, 5-furfuryl-5-isopropylbarbituficacid, fusafungine, glafenine, glucagon, glutethimide, glybuthiazole,griseofulvin, guaiacol carbonate, guaiacol phosphate, halcinonide,hematoprphyrin, hexachlorophene, hexestrol, hexetidine, hexobarbital,hydrochlorothiazide, hydrocodone, ibuproxam, idebenone, indoomethacin,inositol niacinate, iobenzamic acid, iocetamic acid, iodipamide,iomegiamic acid, ipodate, isometheptene, isonoxin,2-isovalerylindane-1,3-dione;

[0091] josamycin, 11-ketoprogesterone, laurocapram, 3-O-lauroylpyridoxoldiacetate, lidocaine, lindane, linolenic acid, liothyronine,lucensomycin, mancozeb, mandelic acid, isoamyl ester, mazindol,mebendazole, mebhydroline, mebiquine, mielarsoprol, melphalan,menadione, menthyl valerate, mephenoxalone, mephentennine, mephenyloin,meprylcaine, mestanolone, mestranol, mesulfen, metergoline, methallatal,methandriol, methaqualone, 3-methylcholanthrene, methylphenidate,17-methyltestosterone, metipranolol, minaprine, myoral, nafialofos,nafiopidil, naphthalene, 2-naphthyl lactate, 2-(2-naphthyloxy)ethan01,naphthyl salicylate, naproxen, nealbarbital, nemadectin, niclosamide,nicoclonate, nicomorphine, nifuroquine, nifuroxazide, nitracrine,nitromersol, nogalamycin, nordazepam, norethandrolone, norgestrienone;

[0092] octavefine, oleandrin, oleic acid, oxazepam, oxazolam, oxeladin,oxwthazaine, oxycodone, oxymesterone, oxyphenistan acetate, paclitaxel,paraherquamide, parathion, pemoline, pentaerythritol tetranitrate,pentylphenol, perphenazine, phencarbamide, pheniramine,2-phenyl-6-chlorophenol, phentlmethylbarbituric acid, phenyloin,phosalone, pbthalylsulfathiazole, phylloquinone, picadex, pifamine,piketopfen, piprozolin, pirozadil, plafibride, plaunotol, polaprezinc,polythiazide, probenecid, progesterone, promegestone, propanidid,propargite, propham, proquazone, protionamide, pyrimethamine,pyrimithate, pyrvinium pamoate;

[0093] quercetin, quinbolone, quizalofo-ethyl, rafoxamide, rescinnamine,rociverine, ronnel salen, scarlet red, siccmn, simazine, simetfide,sobuzoxanie, solan, spironolactone, squalene, stanolone, sucralfate,sulfabenz, sulfaguanole, sulfasalazine, SUlfoxide, sulpiride,suxibuzone, talbutal, terguide, testosterone, tetrabromocresol,tetrandrine, thiacetazone, thiocoichicine, thiocftc acid, thioquinox,thioridazine, thiram, thymyl N-isoamylcarbamate, tioxidazole, tioxolone,tocopherol, tolciclate, tolnafiate, triclosan, triflusal, triparanol;

[0094] ursolic acid, valinomycin, verapamil, vinblastine, vitamin A,vitamin D, vitamin E, xenbucin, xylazine, zaltoprofen, and zearalenone.

[0095] A specific polyacid moiety includes compounds having the formula

[0096] A specific R¹⁵ is alkyl.

[0097] A more specific R¹⁵ is methyl, ethyl, or propyl.

[0098] A more specific R¹⁵ is methyl, or propyl.

[0099] A specific polyol has the formula:

[0100] Specific R² groups are derived from compounds having the formula:

[0101] More specific R² groups are derived from compounds having theformula:

[0102] A Specific R² groups has the formula:

[0103] A specific R¹-R² combination is pentaerythritoltetrakis(3-mercapto-propionate) having the formula:

[0104] A specific R³ group has the formula

[0105] wherein each R¹⁶ is an alkanoyl group having from 2 to about 24carbon atoms.

[0106] A specific R¹⁶ group is an alkanoyl group having from about 6 toabout 18 carbon atoms.

[0107] A more specific R¹⁶ group is an alkanoyl group having from about8 to about 12 carbon atoms.

[0108] A more specific R³ group is

[0109] Specific R⁴ groups are derived from compounds having the formula:

[0110] Specific R⁵ groups are polyethylene ethers or polyethyleneimines.

[0111] Specific polyethylene ethers have arcylene oxide units containingfrom 2 to about 10 carbon atoms.

[0112] Other specific polyethylene ethers have the formula—(O—CH₂—CH₂)_(f)— where f is an integer from about 2 to about 150.

[0113] More specific polyethylene ethers have the formula—(O—CH₂—CH₂)_(f)— where f is an integer from about 50 to about 110.

[0114] Specific polyethylene imines have units containing from 2 toabout 10 carbon atoms.

[0115] Other specific polyethylene imines have the formula—(N(R⁷)—CH₂—CH₂)_(f)— where f is an integer from about 2 to about 150.

[0116] More specific polyethylene imines have the formula—(N(R⁷)—CH₂—CH₂)_(f)— where f is an integer from about 50 to about 110.

[0117] Specific R⁶ group is an alkyl or aryl groups, biotin,streptavidin, sugar moieties, folic acid, amino acids and a peptides.

[0118] A more specific R⁶ groups is the peptide Arg-Gly-Asp (R-G-D) orTyr-Ile-Gly-Ser-Arg (Y-I-G-S-R).

[0119] A more specific R⁶ group is biotin.

[0120] The compounds of the invention can be prepared using proceduresknown to those skilled in the art. A representative synthesis isillustrated in Scheme 1, below.

[0121] Triacid, 1, is reacted with three equivalents of2-(4-amino-phenyl)-ethanol, 2, in the presence of a coupling agent,dicyclocarbdiimide (DCC), to provide the tri-amide triol, 3. the triolis reacted with Mucic acid fatty acid ester (FA=a fatty acid residue) toprovide acid, 5. (Each Y represents the corresponding group aftercompletion of each reaction step.) Acid, 5, is reacted with amine triol,6, by activation of the carboxylic acid with DCC, to provide triolamide, 7. Amide, 8, is reacted with a hydrophilic group such as, apolyethylene or a polyethylene imine to provide the macromolecule, 8.

[0122] Schemes 2 and 2A illustrate the preparation of the acylatedcompounds for use in R³, the hydrophobic portion of the compounds of theinvention. The acids are reacted with an acyl halide, (e.g.,CH₃—(CH₂CH₂)_(n)C(═O)Cl, where m is from 2 to about 8) to provide thepolyacylated products. Alternatively, the acyl halide, (e.g.,CH₃—(CH₂CH₂)_(n)C(═O)Cl, or CH₂═CH—(CH₂CH₂)_(p)C(═O)Cl, where m is from2 to about 8) is reacted with the acid in the presence of pyridine toprovide the polyacylated compounds.

[0123] The macromolecules of the invention are particularly useful forsolubilizing hydrophobic molecules, particularly therapeutic agents thatare hydrophobic in nature. Thus, according to one embodiment of thepresent invention, a therapeutic agent is encapsulated by combining theagent and a plurality of compounds of formula (I) in a solvent, such aswater. If the macromolecule has unsaturated groups, the compounds offormula (I) can be cross-linked to provide an encapsulate of theinvention wherein the therapeutic agent is encapsulated in across-linked macromolecule.

[0124] The encapsulates of the invention that comprise a therapeuticagent can be formulated as pharmaceutical compositions and administeredto a mammalian host, such as a human patient in a variety of formsadapted to the chosen route of administration, i.e., orally orparenterally, by intravenous, intramuscular, topical or subcutaneousroutes.

[0125] Thus, the encapsulates of the invention may be systemicallyadministered, e.g., orally, in combination with a pharmaceuticallyacceptable vehicle such as an inert diluent. They may be incorporateddirectly with the food of the patient's diet. For oral therapeuticadministration, the encapsulates of the invention may be used in theform of elixirs, syrups: and the like.

[0126] The compositions may also contain a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Asyrup or elixir may contain the active compound, sucrose or fructose asa sweetening agent, methyl and propylparabens as preservatives, a dyeand flavoring such as cherry or orange flavor. Of course, any materialused in preparing any unit dosage form should be pharmaceuticallyacceptable and substantially non-toxic in the amounts employed. Inaddition, the encapsulates of the invention may be incorporated intosustained-release preparations and devices.

[0127] The encapsulates of the invention may also be administeredintravenously or intraperitoneally by infusion or injection. Solutionsof the encapsulates can be prepared, for example, in water. Underordinary conditions of storage and use, these preparations may contain apreservative to prevent the growth of microorganisms.

[0128] The pharmaceutical dosage forms suitable for injection orinfusion should be sterile, fluid and stable under the conditions ofmanufacture and storage. The prevention of the action of microorganismscan be brought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars, buffers or sodium chloride.

[0129] Sterile injectable solutions are prepared by incorporating theencapsulates of the invention in the required amount in the appropriatesolvent with various of the other ingredients enumerated above, asrequired, followed by sterilization.

[0130] Encapsulation of molecules according to the invention modifiestransdermal delivery of the molecule. Absorption through the skin cai beincreased or decreased by a factor of up to about 1000. Thus, thepharmaceutical dosage forms of present invention include dosage formssuitable for transdermal delivery, which, in addition to aqueoussolutions, also include aqueous gels. The dosage form may be applieddirectly to the skin as a lotion, cream or salve, or a transdermal drugdelivery device such as a transdermal patch may be employed, in whichthe encapsulated molecule is retained in the active agent reservoir ofthe patch.

[0131] The dose and method of administration will vary from animal toanimal and be dependent upon such factors as the type of animal beingtreated, its sex, weight, diet, concurrent medication, overall clinicalcondition, the particular therapeutic agent employed, the specific usefor which the agent is employed, and other factors which those skilledin the relevant field will recognize.

[0132] Therapeutically effective dosages may be determined by either invitro or i) vivo methods. For each particular dosage form of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill naturally be influenced by the route of administration, thetherapeutic objectives, and the condition of the patient. Thedetermination of effective dosage levels, that is, the dosage levelsnecessary to achieve the desired result, will be within the ambit of oneskilled in the art. Typically, applications of agent are commenced atlower dosage levels, with dosage levels being increased until thedesired effect is achieved.

[0133] A typical dosage might range from about 0.001 mg to about 1,000mg of therapeutic agent, per kg of animal weight. Preferred dosagesrange from about 0.01 mg/kg to about 100 mg/kg, and more preferably fromabout 0.10 mg/kg to about 20 mg/kg. Advantageously, the dosage forms ofthis invention may administered several times daily, and other dosageregimens may also be useful.

[0134] The compounds of formula (I), of the invention may also be usedas thickening agents, lubricants, detergents surfactants, plasticizersand anti-fouling agents. The compounds of formula (I), of the inventionmay be used as an emulsifying, dispersing or stabilizing agent for dyes,cosmetics, pigment and pharmaceutical products. The compounds of formula(I), of the invention are particularly useful as an, emulsifying,dispersing or stabilizing agent in the dyeing of textiles and forencapsulating dyes for cosmetics. The compounds of formula (I), of theinvention are useful as lubricants and as a thickening agents forpaints. The compounds of formula (I), of the invention may also beemployed as an emulsifying, dispersing or stabilizing agent forcomponents of photographic compositions and developers.

[0135] For therapeutic applications, the preferred polymers of theinvention hydrolyze into components known to be biocompatible, e.g.,sugars, fatty acids, amino acids and poly(ethylene glycol). This alsoresults in low cytotoxicity of the polymer and its hydrolysis products.The poly(alkylene oxide) units enhance the immunogenicity of theencapsulate, enabling the hydrophobic molecules to evade the body'simmune system, thereby increasing the circulation time of thehydrophobic molecule. This allows for effective treatment with reducedquantities of the hydrophobic molecule, which, together with theenhanced immunogenicity, prevents or reduces the severity of incidentsof toxic side effects.

[0136] The following non-limiting examples set forth hereinbelowillustrate certain aspects of the invention. All parts and percentagesare by weight unless otherwise noted and all temperatures are in degreesCelsius.

[0137] All PEG's were obtained from Shearwater Polymers (Birmingham,Ala.) and used without further purification. All other chemicals wereobtained from Aldrich (Milwaukee, Wis.), and used without furtherpurification. Analytical grade solvents were used for all the reactions.Methylene chloride, tetrahydrofuran (THF), triethylamine (TEA) anddimethylsulfoxide (DMSO) were distilled. 4-(dimethylamino)pyridiniump-toluenesulfonate (DPTS) was prepared as described by J. S. Moore, S.I. Stupp Macromolecules 1990, 23, 65. ¹H-NMR and spectra were recordedon a Varian 200 MHz or 400 MHz spectrometer. Samples (˜5-10 mg/ml) weredissolved in CDCl₃ or THF-d₄, with the solvent used as an internalreference. IR spectra were recorded on a Mattson Seriesspectrophotometer by solvent casting samples onto a KBr pellet. Thermalanalysis data were determined on a Perkin-Elmer Pyris 1 DSC system,samples (˜10 mg) were heated under dry nitrogen gas. Data were collectedat heating and cooling rates of 5° C./min. Gel permeation chromatography(GPC) was performed on a Perkin-Elmer Series 200 LC system. Dynamiclaser scattering (DSL) measurements were carried on NICOMP particlesizing systems.

EXAMPLES Examples 1-3 Acylation of Mucic Acid Example 1 Mucic AcidPropyl Ester

[0138] To a neat mixture of mucic acid (4.2 g, 20 mmol) and propionylchloride (18 ml, 200 mmol) was added ZnCl₂ (0.28 g, 2.0 mmol). Thereaction mixture was heated at reflux temperature for three hours. Aftercooling, diethyl ether (20 ml) was added to the reaction mixture and thesolution poured onto ice chips (approximately 100 g) with stirring.Additional diethyl ether (80 ml) was added to the mixture and stirringcontinued for 30 minutes more. The ether portion was separated, washedwith water to a neutral pH, dried over anhydrous Na₂SO₄ and evaporatedto dryness. The crude product was purified by recrystallization from acosolvent system of diethyl ether and methylene chloride, collected byvacuum filtration, washed by ice cold methylene chloride and dried at105° C. (12 hours) to constant weight. A white solid having a T_(m), of196° C. was obtained at a 56% yield.

Example 2 Mucic Acid Hexyl Ester

[0139] Mucic acid hexyl ester was prepared as in Example 1, substitutingcaproyl chloride for propionyl chloride. A white solid having a T_(m) of171° C. was obtained at a yield of 68%.

Example 3 Mucic Acid Lauryl Ester

[0140] Mucic acid lauryl ester was prepared as in Example 1,substituting lauryl chloride for propionyl chloride. A white solidhaving a T_(m) of 145° C. was obtained at a yield of 65%.

Examples 4-6 Preparation of Polymer Core Example 4 Propyl Ester

[0141] The mucic acid propyl ester of Example 1(6.0 mmol) and1,1,1-tris(4′-hydroxyphenyl)ethane (0.51 g, 1.7 mmol) were dissolved inanhydrous ethyl ether (150 ml). To the reaction mixture, a solution ofDCC (1.2 g, 6.0 mmol) and DMAP (0.74 g, 6.0 mmol) in 25 ml methylenechloride was added dropwise. After 15 minutes, the DCC side-product(dicyclohexylurea) was removed by suction filtration. The filtrate waswashed with 20 ml portions of 0.1 N HCL (2×) and brine (4×), dried overanhydrous Na₂SO₄, and evaporated to dryness. The crude product waspurified by flash chromatography using ethyl ether: methanol: aceticacid (90:5:5) as eluent. A white solid having a T_(m) of 158° C. wasobtained at 58% yield.

Example 5 Hexyl Ester

[0142] The hexyl ester core molecule was prepared according to themethod of Example 4, substituting the mucic acid hexyl ester of Example2 for the mucic acid propyl ester. A white solid having a T_(m) of 147°C. was obtained at 36% yield.

Example 6 Lauryl Ester

[0143] The lauryl ester core molecule was prepared according to themethod of Example 4, substituting the mucic acid lauryl ester of Example3 for the mucic acid propyl ester. A white solid having a T_(m) of 136°C. was obtained at yield of 33%.

Examples 7-11 Preparation of Final Polymers Example 7 Mucic Acid HexylEster Core Polymer With Triethylene Glycol (TEG) Branches

[0144] To a mixture of the core molecule of Example 5 (0.106 mmol) andmethoxy-terminated triethylene glycol amine (0.351 mmol) in 20 ml ofmethylene chloride at room temperature, DCC (0.351 mmol) and DMAP (0.351mmol) in 2 ml methylene chloride was added dropwise. After three days,the reaction mixture was evaporated to dryness, the residue dissolvedinto 20 ml methanol, and the crude product precipitated from 400 mlpetroleum ether at room temperature. The crude product was firstpurified by flash chromatography using ethyl ether: methanol: aceticacid (90:5:5) as eluent, then further purified by repetitiveprecipitation using methylene chloride as solvent and diethylether/petroleum ether as non-solvent. The ratio between methylenechloride and ethers was progressively changed. A white solvent wasobtained having a T_(m) of 31° C., a T_(d) of 220° C. and M_(W) of 2,400daltons at a yield of 15%.

Example 8 Mucic Acid Hexyl Ester Core Polymer With PEG 2000 Branches

[0145] A mucic acid hexyl ester core polymer with PEG 2000 branches wasprepared according to the method of Example 7, substitutingmethoxy-terminated poly(ethylene glycol)amine (H₂N-m-PEG 2000,M_(w)=2000) for the methoxy-terminated triethylene glycol amine ofExample 7. A white solid was obtained having a T_(m) of 54° C. and aM_(w) of 9,400 daltons at a yield of 25%.

Example 9 Mucic Acid Hexyl Ester Core Polymer With PEG 5000 Branches

[0146] A mucic acid hexyl ester core polymer with PEG 5000 branches wasprepared according to the method of Example 7, substitutingmethoxy-terminated poly(ethylene glycol)amine (H₂N-PEG 5000, M_(w)=5000)for the methoxy-terminated triethylene glycol amine of Example 7. Awhite solid having a T_(m) of 61° C. and a M_(w) of 17,800 daltons wasobtained at 17% yield.

Example 10 Mucic Acid Propyl Ester Core Polymer With PEG 5000 Branches

[0147] Mucic acid propyl ester core polymer with PEG 5000 branches wasprepared according to the method of Example 9, substituting the mucicacid propyl ester core polymer of Example 4 for the mucic acid hexylester core polymer. A white solid was obtained having a T_(m) of 62° C.and a M_(w) of 17,000 daltons at 30% yield.

Example 11 Mucic Acid Lauryl Ester Core Polymer With PEG 5000 Branches

[0148] Mucic acid lauryl ester core polymer with PEG 5000 branches wasprepared according to the method of Example 9, substituting the mucicacid lauryl ester core polymer of Example 6 for the mucic acid hexylester core polymer. A white solid was obtained having a T_(m) of 60° C.and a M_(w) of 19,100 daltons at a yield of 45%.

[0149] For the polymers of Examples 8-11, TGA showed two stages ofdecomposition. The first stage corresponded to cleavage of the corestructures from the ethylene oxide chains (about 200° C.) with theappropriate weight loss, and the second stage corresponded todecomposition of the ethylene oxide chain.

Example 12 Encapsulation Studies

[0150] Lidocaine (50 mg) and the polymer of Example 9 (50 mg) weredissolved in 2.0 ml methylene chloride. The solution was evaporated todryness and the solid residue extensively washed with hexane untillidocaine was no longer detected in the washings. The solid was driedunder vacuum at 25° C. for about 2 hours. A portion (5.0 mg) of thissolid was dissolved into methanol (1.0 ml) to release the entrappedlidocaine, and the lidocaine concentration was quantified by highpressure liquid chromatography (HPLC) according to a calibration curvegenerated from a series of standard solutions ranging from 0.005 to 0.5mg/ml lidocaine. The linearity of the curve indicated a direct,proportional relationship between absorbance and lidocaineconcentration. Using the equation of the lidocaine calibration curve,the amount of lidocaine entrapped in the unimolecular micelle core wasdetermined. PEG with a molecular weight of 5,000 daltons was used as theHPLC control.

[0151] Encapsulation number was defined as the amount of molecules thatcan be entrapped within the polymeric micelles. The values for thepolymers of Example 9, 10 and 11 were 1.0, 0.7 and 1.6 weight %,respectively. The encapsulation number increased as the hydrophobicityof the polymer interior increased.

[0152] The PEG arms of the polymers of the present invention thus form ahydrophilic shell that solubilizes the polymer in water, while the coreforms a hydrophobic microenvironment that encapsulates small hydrophobicmolecules. Unlike conventional micelles, however, the polymeric micellesof the present invention are thermodynamically stable because of thecovalent linkages between the polymer arms. The ability to encapsulatesmall molecules, the enhanced solubility and the lack of aggregationcharacterize the usefulness of these polymers as drug delivery systems.Candidate drugs, of which there are many, have aromatic orheteroaromatic moieties and carbonyl functionalities (e.g., amides andcarboxylates). The biocompatibility and biodegradability of thesepolymers further characterize their utility for drug delivery. Theexcellent water-solubility of these polymers makes intravenous injectionand oral administration of hydrophobic drug molecules possible. Forcontrolled release applications, the small size of these polymers, alongwith their enhanced thermodynamic stability, further characterizes theirutility.

[0153] All publications, patents, and patent documents are incorporatedby reference herein, as though individually incorporated by reference.The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound having formula (I):R¹—((R²)_(a)—(R³)_(b)—(R⁴)_(c)—(R⁵)_(d)—(R⁶)_(e))_(n)  (I) wherein R¹ isa core comprising a polyol or polyacid; each R² independently is adivalent or polyvalent group having the formula —X¹—R⁸—(X^(1a))_(g)—,wherein X¹ and X^(1a) are independently —C(═O)—, —C(═S)—, —O—, —S—,—N(R⁷)— or absent, and each R⁸ is independently —(C₁₋₈)alkylene-,branched —(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-; a is 0 or an integer from 1to about 10; and g is an integer from 1 to about 6; each R³independently is a divalent dicarboxylic acid moiety having the formula—C(═O)—R⁹—C(═O)—, wherein R⁹ is an alkylene or cycloalkylene groupcontaining from 1 to about 15 carbon atoms, substituted with a total offrom 1 to about 10 hydroxy groups, wherein one or more of the hydroxygroups of the dicarboxylic acid are acylated with an acid residue; and bis an integer from 1 to about 10; each R⁴ independently is a divalent orpolyvalent group having the formula —X²—R¹⁰—(X^(2a))_(h)—, wherein X² is—C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent; X^(2a) is —C(═O)—,—C(═S)—, —O, —S—, or —N(R⁷)— and R¹⁰ is —(C₁₋₈)alkylene-, branched—(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-; and c is 0 or an integer from 1 toabout 10; and h is an integer from 1 to 6; each R⁵ independently is agroup having the formula: —R¹²—(R¹¹)_(f)—R¹²—X³—wherein R¹¹ is a sugarmoiety; or a poly(alkylene oxide) or poly(alkylene imine) group havingthe formula —(—X⁴—R¹³)—; wherein R¹³ is —(C₂₋₄₀)alkylene- or branched—(C₃₋₄₀)alkylene-; wherein each R¹³ is independently —C(═O)—, —C(═S)—,—O—, —S—, —N(R⁷)— or absent; each X⁴ is independently —O—, or —N(R⁷)—;and f is an integer from about 2 to about 150; and d is from 1 to about6, each R¹² is independently a bond, —(C₁₋₄₀)alkylene- or branched—(C₁₋₄₀)alkylene-groups, wherein each R¹² is optionally substituted withone or more (e.g., 1, 2, or 3) functional group; and X⁴ is —O—, —S—, or—N(R⁷)—; wherein n is from 2 to 12; provided that a and b are not bothzero; wherein each R⁷ is independently selected from the groupconsisting of hydrogen, and C₍₁₋₄₀₎alkyl group, where the alkyl groupcan be a straight-chain or branched group; and R^(a) and R^(b) are eachindependently hydrogen (C₁₋₈)alkyl, aryl, aryl(C₁₋₈)alkylene; and R⁶ ishydrogen, are —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H (sulfo), —CH₂—OH,—CH₂—OR^(a), —CH₂—O—CH₂—R^(a)—CH₂—NR^(a)R^(b) or a targeting moiety;provided that at least one R⁶ group is a targeting moiety; and e is from1 to about
 6. 2. A compound having formula (I):R¹—((R²)_(a)—(R³)_(b)—(R⁴)_(c)—(R⁵)_(d)—(R⁶)_(e))_(n)  (I) wherein R¹ isa core comprising a polyol or polyacid; each R² independently is adivalent or polyvalent group having the formula —X¹—R⁸—(X^(1a))_(g)—,wherein X¹ and X^(1a) are independently —C(═O)—, —C(═S)—, —O—, —S—,—N(R⁷)— or absent, and each R⁸ is independently —(C₁₋₈)alkylene-,branched —(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-; a is an integer from 1 toabout 10; and g is an integer from 1 to about 6; each R³ independentlyis a divalent dicarboxylic acid moiety having the formula—C(═O)—R⁹—C(═O)—, wherein R⁹ is an alkylene or cycloalkylene groupcontaining from 1 to about 15 carbon atoms, substituted with a total offrom 1 to about 10 hydroxy groups, wherein one or more of the hydroxygroups of the dicarboxylic acid are acylated with an acid residue; and bis an integer from 1 to about 10; each R⁴ independently is a divalent orpolyvalent group having the formula —X²—R¹⁰—(X^(2a))_(h)—, wherein X² is—C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent; X^(2a) is —C(═O)—,—C(═S)—, —O—, —S—, or —N(R⁷) and R¹⁰ is —(C₁₋₈)alkylene-, branched—(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-; and c is 0 or an integer from 1 toabout 10; and h is an integer from 1 to 6; each R⁵ independently is agroup having the formula: —R¹²—(R¹¹)_(f)—R¹²—X³— wherein R¹¹ is a sugarmoiety; or a poly(alkylene oxide) or poly(alkylene imine) group havingthe formula —(—X⁴—R¹³)—; wherein R¹³ is —(C₂₋₄₀)alkylene- or branched—(C₃₋₄₀)alkylene-; wherein each X³ is independently —C(═O)—, —C(═S)—,—O, —S—, —N(R⁷)— or absent; each X⁴ is independently —O—, or —N(R⁷)—;and f is an integer from about 2 to about 150; and d is from 1 to about6; each R¹² is independently a bond, —(C₁₋₄₀)alkylene- or branched—(C₁₋₁₀)alkylene-groups, wherein each R¹² is optionally substituted withone or more (e.g., 1, 2, or 3) functional groups; and X⁴ is —O—, —S—, or—N(R⁷)—; wherein n is from 2 to 12; provided that a and b are not bothzero; wherein each R⁷ is independently selected from the groupconsisting of hydrogen, and C₍₁₋₄₀₎alkyl group, where the alkyl groupcan be a straight-chain or branched group; and R^(a) and R^(b) are eachindependently hydrogen (C₁₋₈)alkyl, aryl, aryl(C₁₋₈)alkylene; and R⁶ ishydrogen, are —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H (sulfo), —CH₂—OH,—CH₂OR^(a), —CH₂—O—CH₂—R^(a), —CH₂—NR^(a)R^(b) or a targeting moiety;and e is from 1 to about
 6. 3. A compound having formula (I):R¹—((R²)_(a)—(R³)_(b)—(R⁴)_(c)—(R⁵)_(d)—(R⁶)_(e))_(n)  (I) wherein R¹ isa core comprising a polyol or polyacid; each R² independently is adivalent or polyvalent group having the formula —X¹—R⁸—(X^(1a))_(g)—,wherein X¹ and X^(1a) are independently —C(═O)—, —C(═S)—, O—, —S—,—N(R⁷)— or absent, and each R⁸ is independently —(C₁₋₈)alkylene-,branched —(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-; a is 0 or an integer from 1to about 10; and g is an integer from 1 to about 6; each R³independently is a divalent dicarboxylic acid moiety having the formula—C(═O)—R⁹—C(═O)—, wherein R⁹ is an alkylene or cycloalkylene groupcontaining from 1 to about 15 carbon atoms, substituted with a total offrom 1 to about 10 hydroxy groups, wherein one or more of the hydroxygroups of the dicarboxylic acid are acylated with an acid residue; and bis an integer from 1 to about 10; each R⁴ independently is a divalent orpolyvalent group having the formula —X²—R¹⁰—(X^(2a))_(h)—, wherein X² is—C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent; X^(2a) is —C(═O)—,—C(═S)—, —O—, —S—, or —N(R⁷)— and R¹⁰ is —(C₁₋₈)alkylene-, branched—(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-; and c is 0 or an integer from 1 toabout 10; and h is an integer from 1 to 6; each R⁵ independently is agroup having the formula: —R¹²—(R¹¹)_(f)—R¹²—X³— wherein R¹¹ is a sugarmoiety; or a poly(alkylene oxide) or poly(alkylene imine) group havingthe formula —(—X⁴—R¹³)—; wherein R¹³ is —(C₂₋₄₀)alkylene- or branched—(C₃₋₄₀)alkylene-; wherein each X³ is independently —C(═O)—, —C(═S)—,—O—, —S—, —N(R⁷)— or absent; each X⁴ is independently —O—, or —N(R⁷)—;and f is an integer from about 2 to about 150; and d is from 1 to about6; each R¹² is independently a bond, —(C₁₋₄₀)alkylene- or branched—(C₁₋₄₀)alkylene-groups, wherein each R¹² is optionally substituted withone or more (e.g., 1, 2, or 3) functional groups; and X⁴ is —O—, —S—, or—N(R⁷)—; wherein n is from 2 to 12; provided that a and b are not bothzero; wherein each R⁷ is independently selected from the groupconsisting of hydrogen, and C₍₁₋₄₀₎alkyl group, where the alkyl groupcan be a straight-chain or branched group; and R^(a) and R^(b) are eachindependently hydrogen (C₁₋₈)alkyl, aryl, aryl(C₁₋₈)alkylene; and R⁶ ishydrogen, are —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H (sulfo), —CH₂—OH,—CH₂—OR^(a), —CH₂—O—CH₂—R^(a), —CH₂—NR^(a)R^(b) or a targeting moiety;and e is from 1 to about
 6. 4. A compound having formula (I):R¹—((R²)_(a)—(R³)_(b)—(R⁴)_(c)—(R⁵)_(d)—(R⁶)_(e))_(n)  (I) wherein R¹ isa core comprising a polyacid moiety having the formula

or a pentaerythritol polyol having the formula

wherein each R² independently is a divalent or polyvalent group havingthe formula —X¹—R⁸—(X^(1a))_(g)—, wherein X¹ and X^(1a) areindependently —C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷)— or absent, and each R⁸is independently —(C₁₋₈)alkylene-, branched —(C₁₋₈)alkylene- or—(C₆₋₁₀)aryl-; a is 0 or an integer from 1 to about 10; and g is aninteger from 1 to about 6; each R³ independently is a divalentdicarboxylic acid moiety having the formula —C(═O)—R⁹—C(═O)—, wherein R⁹is an alkylene or cycloalkylene group containing from 1 to about 15carbon atoms, substituted with a total of from 1 to about 10 hydroxygroups, wherein one or more of the hydroxy groups of the dicarboxylicacid are acylated with an acid residue; and b is an integer from 1 toabout 10; each R⁴ independently is a divalent or polyvalent group havingthe formula —X²R¹⁰(X^(2a))_(h)—, wherein X² is —C(═O)—, —C(═S)—, —O—,—S—, —N(R⁷)— or absent; X^(2a) is —C(═O)—, —C(═S)—, —O—, —S—, or —N(R⁷)—and R10 is —(C₁₋₈)alkylene-, branched —(C₁₋₈)alkylene- or —(C₆₋₁₀)aryl-;and c is 0 or an integer from 1 to about 10; and h is an integer from 1to 6; each R⁵ independently is a group having the formula:—R¹²—(R¹¹)_(f)—R¹²—X³— wherein R¹¹ is a sugar moiety; or a poly(alkyleneoxide) or poly(alkylene imine) group having the formula —(—X⁴—R¹³)—;wherein R¹³ is —(C₂₋₄₀)alkylene- or branched —(C₃₋₄₀)alkylene-; whereineach X³ is independently —C(═O)—, —C(═S)—, —O—, —S—, —N(R⁷_or absent;each X⁴ is independently —O—, or —N(R⁷)—; and f is an integer from about2 to about 150; and d is from 1 to about 6; each R¹² is independently abond, —(C₁₋₄₀)alkylene- or branched —(C₁₋₄₀)alkylene-groups, whereineach R¹² is optionally substituted with one or more (e.g., 1, 2, or 3)functional groups; and X⁴ is —O—, —S—, or —N(R⁷)—; wherein n is from 2to 12; provided that a and b are not both zero; wherein each R⁷ isindependently selected from the group consisting of hydrogen, andC₍₁₋₄₀₎alkyl group, where the alkyl group can be a straight-chain orbranched group; and R^(a) and R^(b) are each independently hydrogen(C₁₋₈)alkyl, aryl, aryl(C₁₋₈)alkylene; and R⁶ is hydrogen, are —OH,—OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H (sulfo), —CH₂—OH, —CH₂—OR^(a),—CH₂—O—CH₂—R^(a), —CH₂—NR^(a)R^(b) or a targeting moiety; and e is from1 to about
 6. 5. The compound of any one of claims 14, wherein R² hasthe formula:


6. The compound of any one of claims 1-5, wherein R² has the formula:


7. The compound of any one of claims 1-6, wherein R² has the formula:


8. The compound of any one of claims 1-7, wherein the R¹-R² combinationhas the formula:


9. The compound of any one of claims 1-8, wherein R³ has the formula

wherein each R¹⁶ is an alkanoyl group having from 2 to about 24 carbonatoms.
 10. The compound of any one of claims 1-9, wherein R³ is


11. The compound of any one of claims 1-10, wherein R¹⁶ is an alkanoylgroup having from about 6 to about 18 carbon atoms.
 12. The compound ofany one of claims 1-11, wherein R¹ has from about 2 carbons to about 20carbons.
 13. The compound of any one of claims 1-12, wherein R¹ has fromabout 3 carbons to about 12 carbons.
 14. The compound of any one ofclaims 1-13, wherein the R¹ moeity has from about 4 carbons to about 10carbons.
 15. The compound of any one of claims 1-3 or 5-14, wherein R¹is a cycloaliphatic polyol.
 16. The compound of any one of claims 1-15,wherein R¹ is a polyacid having the formula

or a polyol having the formula

wherein each R¹⁴ is —(R²)_(a)—(R³)_(b)—(R⁴)_(c)—(R⁵)_(d)—(R⁶)_(c); andwherein R¹⁵ is hydrogen or (C₁₋₆)alkyl; and R², R³, R⁴, R⁵, a, b, c, andd, are as defined hereinabove.
 17. The compound of claim 16, where R¹⁵is alkyl.
 18. The compound of claim 17, where R¹⁵ is methyl, ethyl, orpropyl.
 19. The compound of claim 18, where R¹⁵ is methyl, or propyl.20. The compound of any one of claims 1-16, wherein R¹ comprises a corehaving the formula:


21. The compound of any one of claims 1-20, wherein R² is—C(═O)—CH₂—CH₂—S—.
 22. The compound of any one of claims 1-16 or 20-21,wherein the R¹-R² combination is pentaerythritoltetrakis(3-mercaptopropionate).
 23. The compound of any of claims 1-16or 20-22, wherein the R¹ moeity comprises from about 2 to about 20hydroxy groups.
 24. The compound of any one of claims 1-16 or 20-23,wherein the R¹ moeity comprises from about 2 to about 12 hydroxy groups.25. The compound of any one of claims 1-16 or 20-24, wherein the R¹moeity comprises from about 2 to about 10 hydroxy groups.
 26. Thecompound of any one of claims 1-25, wherein the R¹ moeity is substitutedwith one or more carboxy groups.
 27. The compound of any of claims 1-26,wherein the R¹ moeity is substituted with two carboxy groups.
 28. Thecompound of any one of claims 1-27, wherein the R¹ moeity is substitutedwith one carboxy group.
 29. The compound of any one of claims 1-28,wherein R⁴ has the formula:


30. The compound of any one of claims 1-29, wherein R⁵ has the formula:—R¹²—(O—R¹³)_(f)—R¹²—, wherein R¹³ is a 1 to 20 carbon straight-chain orbranched alkyl group, wherein each R¹² is optionally substituted withone or more functional groups selected from the group consisting of —OH,—OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H, —CH₂OR^(a), —CH₂—O—CH₂—R^(a),—CH₂CO₂H, —CH₂SO₃H, —O—C(═O)—CH₂—CH₂—C(═O)—O— or —CH₂—NR^(a)R^(b); Q is—O—, —S—, and —NR^(a)—; and R¹² is a 1 to 10 carbon straight-chain orbranched divalent alkylene group; R^(a) and R^(b) are each independentlyhydrogen (C₁₋₆)alkyl, aryl, aryl(C₁₋₈)alkylene f is an integer from 2 to150, inclusive.
 31. The compound of any one of claims 1-31, wherein theR is a polyethylene ether having between about 2 and about 110 alkyleneoxide repeating units.
 32. The compound of any one of claims 1-31,wherein the alkylene oxide units containing from 2 to about 10 carbonatoms and may be straight chained or branched.
 33. The compound of anyone of claims 1-31, wherein the alkylene oxide units contain from 2 to 4carbon atoms and may be straight chained or branched.
 34. The compoundof any one of claims 1-31 wherein R⁵ is linked to R¹ through an ester,thioester, or amide linkage.
 35. The compound of any one of claims 1-31wherein R⁵ is linked to R¹ through an ester or amide linkage.
 36. Thecompound of any one of claims 1-29, wherein R⁵ has the formula:—R¹²—(N(R⁷)—R¹³)_(f)—R¹²—, wherein each R¹² and R¹³ are independently a1 to 20 carbon straight-chain or branched alkyl group, wherein each R¹²is optionally substituted with one or more functional groups selectedfrom the group consisting of —OH, —OR^(a), —NR^(a)R^(b), —CO₂H, —SO₃H,—CH₂—ORa, —CH₂—O—CH₂—R^(a), —CH₂CO₂H, —CH₂SO₃H,—O—C(═O)—CH₂—CH₂—C(═O)—O— or —CH₂—NR^(a)R^(b); Q is —O—, —S—, and—NR^(a)—; and R¹² is a 1 to 10 carbon straight-chain or brancheddivalent alkylene group; R^(a) and R^(b) are each independently hydrogen(C₁₋₆)alkyl, aryl, aryl(C₁₋₈)alkylene f is an integer from 2 to 150,inclusive.
 37. The compound of any one of claims 1-29 or 36, wherein R⁵is a polyethylene imine having between about 2 and about 110 repeatingunits.
 38. The compound of any one of claims 1-29 or 36-37, wherein thepolyethylene imine has units contain from 2 to about 10 carbon atoms.39. The compound of any one of claims 1-38, wherein R⁶ is alkyl, aryl,biotin, streptavidin, sugar moieties, folic acid, amino acids orpeptides.
 40. The compound of any one of claims 1-39, wherein is thepeptide Arg-Gly-Asp (R-G-D) or Tyr-Ile-Gly-Ser-Arg (Y-I-G-S—R).
 41. Thecompound of any one of claims 1-40, wherein R⁶ is biotin
 42. Thecompound of any one of claims 1-41, wherein the acid residue comprisesfrom about 2 to about 24 carbon atoms.
 43. The compound of any one ofclaims 1-42, wherein the acid residue comprises from about 6 to about 18carbon atoms.
 44. The compound of claim 1 wherein the acid residuecomprises caprylic, capric, lauric, myristic, myristoleic, palmitic,palmitoleic, stearic, oleic, linoleic, eleostearic, arachidic, behenic,erucic acid, or a mixture thereof.
 45. The compound of any of claims1-44, wherein the functional groups are —OH, —ORa, —NRaRb, —CO2H, —SO3H(sulfo), —CH2—OH, —CH2—ORa, —CH2-O-CH2-Ra, or —CH2-NRaRb.
 46. Anencapsulate comprising a molecule surrounded or partially surrounded byat least one compound of formula (I), as described in any one of claims1-45.
 47. An encapsulate comprising a therapeutic agent surrounded orpartially surrounded by at least one compound of formula (I), asdescribed in any one of claims 1-45.
 48. A composition comprising atleast one compound of formula (I) as described in any one of claims 1-45in a solvent.
 49. The composition of claim 48, wherein the solventcomprises an organic solvent.
 50. The composition of claim 48, whereinthe solvent comprises water.
 51. The composition of claim 48, whereinthe solvent is water.
 52. A method for preparing an encapsulate asdescribed in claim 47, comprising combining at least one compound offormula (I), as described in any one of claims 1-45, and a molecule in asolvent; and allowing the compound of formula (I) to aggregate aroundthe molecule, to provide the encapsulate
 53. A pharmaceuticalcomposition comprising an encapsulate as described in claim 45; and apharmaceutically acceptable carrier.
 54. A method for delivering atherapeutic agent to an animal in need of treatment with the agentcomprising administering an encapsulate as described in claim 45 to theanimal.